PROJECT SUMMARY Rheumatoid arthritis (RA) has been considered an independent risk factor for coronary heart disease (CHD), and mortality from CHD in RA is double what it is in the general population. Mechanisms of CHD in the general population are not fully known, but it is proposed that in addition to its inflammatory features, CHD may have autoimmune features as well. Using RA and RA-related autoimmunity as model to understand the contributions of autoantibodies, changes in autoantibodies, and genetic predisposition to the development of these autoimmune features could provide new insights into CHD and myocardial disease in the general population, thus providing new ways to monitor, prevent, and potentially intervene. In the setting of rheumatologic diseases, antibodies to citrullinated protein antigens (ACPA) have been linked to cardiovascular disease (CVD), and these findings have been extended to other select patient populations without RA. Citrullination of proteins occurs in several normal cellular processes, including inflammation, apoptosis, and cellular differentiation. While citrullination is normal, autoantibodies to these citrullinated proteins are abnormal, and elicit a self-directed immune response. Citrullinated proteins have been located in the myocardial interstitium among diverse disease states, including RA, and antibodies against these citrullinated myocardial proteins may induce myocardial remodeling. RA-related autoantibodies, including ACPA, occur in individuals at least 15 years prior to onset of RA, and in individuals who may never develop RA. My preliminary data from my K01-supported study of 1232 MESA participants found significant associations between the number of positive ACPA and lower left ventricular ejection fraction as well as with incident angina and myocardial infarction. It is unknown, however, whether changes in ACPA levels over time are associated with worse CVD outcomes. This proposal aims to further investigate relationships of longitudinal changes in ACPA with myocardial structure and function. The major histocompatibility complex (MHC) is a well-recognized immune response gene that controls the magnitude and specificity of antibody production. In humans, the MHC HLA-DRB1 shared epitope alleles predisposes for ACPA development, and have been associated with vascular injury markers in a population of RA-free first-degree relatives of RA patients. In individuals possessing the HLA-DRB1 alleles, the associations with cardiac abnormalities may be stronger, and thus offer an opportunity for screening and earlier surveillance of cardiac structure and function should an individual possess these alleles. Thus, the goal of this proposal is to fully characterize whether ACPA are associated with markers of myocardial disease, and whether possessing the HLA-DRB1 alleles modifies these associations.